Mavrilimumab at the 2020 EULAR Online Meeting

Mavrilimumab has my interest for about a decade now. There have been two studies at the 2020 EULAR Online Meeting. I am suprised! My last entry here on the blog concerning mavrilimumab dates back to January 17^th 2019 under the title: „Mavrilimumab discontinued“ [1].

Mavrilimumab is a human monoclonal antibody tht targets the GMCSF [Granulocyte macrophage colony stimulating factor] receptor and alpha-chain.

G. De Luca and colleagues presented the following study [2]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The study is single-center, non-randomized, open-label, single active arm intervention (N=13) with comparison to “contemporaneous patients (N=26) with similar baseline characteristics”. The patients in the active arm received a non-disclosed single dose of mavrilimumab. In “results” the authors tell us: “Death occurred in 0% (n=0/13)

of mavrilimumab recipients and 27% (n=7/26) of comparison-group patients (log rank p=0.046) during the 28-day follow-up. 100% (n=13) of mavrilimumab recipients and 65% (n=17) of comparison-group patients achieved clinical improvement (p=0.018) at Day 28, with earlier improvement (median 8.0 [IQR, 5.0–11.0] days vs 18.5 [11.0–NE] days) (p<0 -="" .001="" 1.0="" 14="" 61="" 7.0="" 91="" by="" compared="" comparison="" controls="" day="" days="" faster="" febrile="" fever="" group="" had="" in="" lang="en-US" mavrilimumab="" median="" n="11/18" ne="" of="" p="0・009)." patients="" recipients.="" recipients="" resolution="" resolved="" respectively="" span="" the="" to="" versus="" vs="" was="">was well tolerated in all patients.” The authors concluded: “Patients with severe COVID-19 pneumonia and systemic hyper-inflammation who received treatment with mavrilimumab had better clinical outcomes compared to patients receiving routine care. … Randomized controlled trials are warranted to confirm our findings.”

It is unclear, how patients were chosen to get mavrilimumab. Did the “26 contemporaneous patients with similar baseline characteristics” also showed “severe COVID-19 pneumonia (as evaluated by CT scanning), hypoxia (PaO2:FiO2 ratio ≤ 300 mmHg), and systemic hyper-inflammation (increased C-reactive protein [CRP] ≥ 100 mg/mL and/or ferritin ≥ 900 μg/L, increased lactate dehydrogenase [LDH])”?

In former studies the most common adverse event of mavrilimumab had been a decrease in CO diffusing capacity. So why choose an investigational drug instead of an IL-6-inhibitor already on the market in other indications?

The study by M. C. Cid and colleagues is a cell sttudy{3]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The authors looked at “expression of GM-CSF and GM-CSF-Rα proteins in temporal artery biopsies (TABs) from GCA and controls (patients with suspected but not confirmed GCA and a negative TAB).” The authors concluded: “Increased GM-CSF, GM-CSF-Rα, and downstream pathway-associated protein levels in GCA biopsies were consistent with previously-observed increased transcriptome signature. Expression of genes associated with inflammatory cells was suppressed by mavrilimumab in cultured GCA arteries. These data implicate the GM-CSF pathway in GCA pathophysiology and increase confidence in rationale for targeting the GM-CSF pathway in GCA.”

Adis Insight reports a phase II trial in B-cell lymphoma (Second-line therapy or greater, Combination therapy) in the second half of 2020 (17.06.2020) and phase II trial in Giant cell arteritis in Australia, Belgium, Croatia, Estonia, Germany, Italy, Ireland, Netherlands, New Zealand, Poland, Serbia, Slovenia, Spain, USA and United Kingdom (NCT03827018) (13.03.2020) [4].

I am still not convinced that mavrilimumab will become a drug in rheumatology. Kiniksa Pharmaceuticals should clarify how comparable the patients in the COVID-19 study were and why there hasn't been a randomization.

Links and References:

[1] http://rheumatologe.blogspot.com/2019/01/mavrilimumab-discontinued.html

[2] G. De Luca1,2, G. Cavalli1,2, C. Campochiaro1,2, E. Della Torre1,2, P. Angelillo1, A. Tomelleri1,2, N. Boffini1, S. Tentori1, F. Mette1,2, P. Rovere-Querini1,2, A. Ruggeri1, T. D’aliberti1, P. Scarpelllini1, G. Landoni1,2, F. De Cobelli1,2, J. F. Paolini3, A. Zangrillo1,2, M. Tresoldi1, B. C. Trapnell4, F. Ciceri1, L. Dagna1,2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.6858

[3] M. C. Cid1, S. Muralidharan2, M. Corbera-Bellalta1, G. Espigol-Frigole1, J. Marco Hernandez1, A. Denuc3, R. Rios-Garces1, N. Terrades-Garcia1, J.

F. Paolini2, A. D’andrea2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.4984

[4] https://adisinsight.springer.com/drugs/800014624

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Mavrilimumab discontinued

Adisinsight updated its information on Mavrilimumab on Dec. 12^th 2018. I’ve just checked this source as I wanted to know more about the fate of Mavrilimumab after having listened to a talk by Prof. G.R. Burmester, one of the chief investigators on Mavrilimumab, last weekend.

Mavrilimumab is a human MAB for the treatment of rheumatoid arthritis. It targets the GMCSF [Granulocyte macrophage colony stimulating factor] receptor and alpha-chain. I’ve written about Mavrilimumab for the first time after the 2012 EULAR Meeting in Berlin.

I already harbored concerns about the drug: “Mavrilimumab did better than placebo, but the effect didn't last as long as the follow-up period after stopping the drug. The most common adverse events had been a decrease in CO diffusing capacity. Did any reader, who worked on studies, ever have to monitor CO diffusing capacity? As I haven't, this point leaves me a little bit uneasy.” Or: “My opinion: this doesn't seem to be the start of a success story. But still, as we need new drugs: All the best, Mavrilimumab!”

In January 2018 ME Weinblatt and colleagues published study details on: “A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis.” The authors concluded: “The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well-tolerated in patients who had shown an inadequate response to DMARDs and/or other anti-TNF agents.”

In June 2017 GR Burmester and colleagues published study details on: “A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis.” The authors concluded: “Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential.” Oh, with persuasive therapeutic potential! We’ll look into the persuasion quickly!

What is the news on this persuasive therapeutic potential? What does Adis Insight tell us? The indication of rheumatoid arthritis is discontinued. Adis Insight: “The US FDA places a clinical hold on a submitted IND application for a phase II trial in Giant cell arteritis, as additional information has been requested regarding the delivery device to be used in the trial”.

I’m still not convinced that Mavrilimumab could be a drug to treat inflammatory rheumatic diseases, though I am in favor for new ways of action as we already have enough TNF-alpha-inhibitors or IL-6-inhibitors. Maybe GMCSF [Granulocyte macrophage colony stimulating factor] simply isn’t a good target. Let’s hope that other targets work better.

Links:

https://adisinsight.springer.com/drugs/800014624

https://rheumatologe.blogspot.com/2012/07/mavrilimumab-at-eular-2012.html

https://www.ncbi.nlm.nih.gov/pubmed/28941039

https://www.ncbi.nlm.nih.gov/pubmed/28213566

https://rheumatologe.blogspot.com/2014/06/mavrilimumab-at-eular-2014-meeting-in.html

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Biosimilars und Biologika auf dem DGRh Kongress 2017 in Stuttgart

Warum ist die Politik so daran interessiert, warum Krankenkassen, Patientenverbände, Fachgesellschaften? Weil sie zuvor ihre Hausaufgaben nicht gemacht haben. Denn sie haben der Preisexplosion nicht Einhalt geboten. Das fing schon vor den Biologika an, aber hierbei ist es doch besonders offensichtlich – und ein Ende ist da nicht in Sicht, wenn wir an die small molecules wie Tofacitinib oder Baricitinib denken. So steigen die Preise weiter an. Der Markt wird immer unüberschaubarer.

Biosimilars kommen wie Innovationen daher, als hätte die Welt darauf gewartet, aber es sind schließlich nur  Imitate; die entscheidenden Ideen haben andere gehabt und in Studien die Wirksamkeit nachgewiesen. Die  Patienten jedenfalls werden damit überfordert. Insbesondere wo es neben Biosimilars auch schon Bioidenticals gibt. Auch wenn ich nicht auf Biosimilars gewartet habe, werde ich sie denooch anwenden, besser anwenden müssen.

Welche Biosimilars haben wir denn? Welche Biologika wurden denn vorgestellt? Gab es funkelnagelneue Bio***s? In dieser Übersicht werde ich mich auf den Einsatz dieser Medikamentengruppe in der Therapie der rheumatoiden Arthritis, der Psoriasisarthritis und den seronegatiben Spondyloarthritiden beschränken.

Biosimilar-Kandidaten zu Humira® (Adalimumab) BI 695501 von Boehringer Ingelheim - ENCORE.42 (Encore sind Poster, die bereits anderswo gezeigt wurden) - das Poster beschäftigt sich mit dem Autoinjektor. Encore.47 beschäftigt sich mit Wirksamkeit und Nebenwirkung und findet keinen wesentlichen Unterschied.

Ansonsten fanden sich viele Poster zu Secukinumab, aber auch Daten zu Tocilizumab, Certolizumab, Canakinumab, Sarilumab, Abatacept, Golimumab, Rituximab, Ixekizumab und Infliximab.

H. Kellner präsentierte Daten aus seiner Schwerpunktpraxis (EV.13): " Hohe Patientenakzeptanz bei Neueinstellung oder Umstellung von Originalabiologika (Enbrel, Remicade) auf Biosimilar-TNF Ak". Die Arbeit hat nur geringe Fallzahlen. In der Schlussfolgerung lesen wir: "Den angesprochenen Patienten ist die Möglichkeit einer substanziellen Kostenersparnis bei Einsatz von Biosimilar durchaus bewußt und ein wesentliches Element der Bereitschaft selbst Biosimilars zu verwenden." Das kann ich so aus den Ergebnissen nicht herauslesen. Ob eine Kostenersparnis dauerhaft gegenüber den Originalherstellern bestehen bleibt, muss die Zukunft zeigen, denn es wird wahrscheinlich zu Festpreisen kommen.

Zusammenfassend spielen die Biosimilars in der Wissenschaft eine untergeordnete Rolle. Das liegt in der Natur der gesetzlichen Bestimmungen, denn es muss nur der Nachweis von gleicher Effektivität und Nebenwirkung zum Orinalpräparat in einer Indikation nachgewiesen werden. Das sollte auch leicht möglich sein, wenn die Strukturgleichheit gegeben ist - und davon ist auszugehen. Für Infliximab haben wir die Biosimilars Remsima®, Inflectra® und Flixabi®, wovon Remsima® und Inflectra® bioidentisch sind, d.h. sie haben einen Hersteller und zwei Vertreiber. Für Etanercept haben wir die Biosimilars Benepali® und Erelzi™. Für Rituximab ist das Biosimilar Truxima® zugelassen. Für Adalimumab ist das Biosimilar Amjevita™ in den USA zugelassen und wird neben anderen hier in der nahen Zulunft erwartet [1].

Für die o.g. Originalpräparate ist eine Fülle von neuen Daten veröffentlicht worden. Allerdings habe ich nichts zu Mavrilimumab und Vobarilizumab gefunden.

Links:

[1] http://rheumatologe.blogspot.de/2016/12/possible-problems-with-piosimilars.html

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Mavrilimumab at the 2017 EULAR Annual Meeting in Madrid

I’ve written quite a few times about mavrilimumab on this blog. The blogpost on “Mavrilimumab at the EULAR 2012” [1] attracted about 9000 visitors. And I’ve also written about mavrilimumab in Chinese [2]. So I might say that I’m interested in mavrilimumab.

Mavrilimumab is a human granulocyte-macrophage colony-stimulating factor receptor-α (GM–CSFR-α) monoclonal antibody. At the 2017 EULAR Annual Meeting we’ve only seen one study.

G. Burmester and colleagues presented [3]: “RESULTS OF A LONGITUDINAL REVIEW OF PULMONARY FUNCTION AND SAFETY DATA IN A PHASE IIB CLINICAL PROGRAMME TESTING GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM–CSF) RECEPTOR ANTAGONIST MAVRILIMUMAB FOR TREATMENT OF RHEUMATOID ARTHRITIS (RA)”. The authors concluded: “We believe this is the most comprehensive longitudinal study of pulmonary function in a clinical RA programme.” O.K., but other seems to do fine without the need to such testing. And after 5 long years we’re still in phase 2b. The authors also concluded: “… its acceptable safety profile advocates initiation of Phase III studies with mavrilimumab. Further studies are now required to fully characterise pulmonary function over time in RA.” Further studies on pulmonary function!

My opinion in 2012: “this doesn't seem to be the start of a success story”. Clinical Trials lists 6 studies on mavrilimumab, which are completed or have been terminated [4]. In German we have the word “dümpeln”, which means “to bob up and down” or “to stagnate”. Mavrilimumab dümpels. But maybe the sponsor will initiate a phase 3 study.

Links and References:

[1] http://rheumatologe.blogspot.de/2012/07/mavrilimumab-at-eular-2012.html

[2] http://rheumatologe.blogspot.de/2014/02/mavrilimumab.html

[3] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 564 / Session: Rheumatoid arthritis - other biologic treatment , (Poster Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.3131

[4] https://clinicaltrials.gov/ct2/results?term=mavrilimumab&Search=Search

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